Denileukin Diftitox Research Articles

Novel Monoclonal Antibodies for the Treatment of Chronic Lymphocytic Leukemia

For many years, alkylating agents and purine nucleoside analogs (PNA) have been considered the drug of choice for treatment of chronic lymphocytic leukemia (CLL). More recently the introduction of monoclonal antibodies (mAb), especially rituximab directed against CD20 and alemtuzumab directed against CD52, has renewed interest in CLL therapy. Over the last few years, several new mAbs directed against lymphoid cells have been developed and investigated in preclinical studies and clinical trials. Some of them are highly active in CLL. New mAbs directed against CD20 include human mAb ofatumumab (HuMax CD20), IMMU-106 (hA20) which has a >90% humanized framework and GA-101, a novel third - generation fully humanized and optimized mAb. These agents are highly cytotoxic against B-cell lymphoid cells and are evaluated in CLL. Lumiliximab (anti-CD23 mAb) is a genetically engineered macaque-human immunoglobulin (Ig) A1. This antibody showed high activity and good tolerability in phase I clinical trial and is evaluated in phase I/II clinical trials as a single agent and in combination. Epratuzumab is a humanized anti-CD22 mAb currently used in clinical trials for treatment of non-Hodgkin lymphoma and autoimmune disorders. Further studies are needed to elucidate the role of this agent in CLL. Apolizumab (HU1D10) is a humanized IgG1 antibody specific for a polymorphic determinant found on the HLA-DRbeta chain. Preclinical and early clinical studies suggest that this mAb has some activity in CLL. HCD122 (CHIR-12.12) and SGN-40 are anti-CD40 mAbs which induce cytotoxicity against CLL cells. Phase I study has shown a favorable safety profile and some activity of HCD122 in pretreated CLL patients. Immunotoxins, especially BL22, LMP-2 and denileukin diftitox, are also being evaluated in lymphoid malignancies and seem to be active in CLL. Finally, antiangiogenic mAbs, especially bevacimzumab, have a potential therapeutic role in this disease. In this review, new mAbs, potentially useful in CLL are presented.

Comparative methodologies of regulatory T cell depletion in a murine melanoma model

There has been recent interest in the depletion of regulatory T cells (Tregs) as part of a multi-faceted approach to the immunotherapy of melanoma patients. This is in part due recent findings that convincingly show that Tregs are an integral part of regulating and even suppressing an immune response to growing tumor cells. We therefore compared three methods of Treg depletion and/or elimination, utilizing low dose cyclophosphamide (CY), a specific antibody directed against the IL-2 receptor found on Tregs (PC61) and the use of denileukin diftitox (DD), which is a fusion protein designed to have a direct cytocidal action on cells which express the IL-2 receptor. We show that CY administration resulted in the highest reduction in Tregs among the three reagents. However, the reduction in Tregs with CY was also associated with the concomitant reduction of CD8(+) T cells and a lack of tumor antigen priming. Utilization of DD resulted in a > 50% Treg cell reduction without parallel cytocidal effects upon other T cell subsets but did not enhance anti-tumor immunity against B16 melanoma. Lastly, the PC61 showed a moderate reduction of Tregs that lasted longer than the other reagents, without a reduction in the total number of CD8(+) T cells. Furthermore, PC61 treatment did not abrogate tumor antigen-specific immunity elicited by dendritic cells (DC). We therefore conclude that PC61 administration was the most effective method of reducing Tregs in a murine melanoma model in addition to providing evidence of a synergistic effect when combined with DC-based immunotherapy.

Cutaneous γ/δ T-Cell Lymphoma Treated with Radiation and Denileukin Diftitox

Cutaneous γ/δT-cell lymphoma (CGD-TCL) is a rare and usually fatal lymphoma that is generally resistant to chemotherapy and radiation. It has recently been included as a provisional entity in the combined 2005 World Health Organization—European Organization for Research and Treatment of Cancer consensus classification. Subcutaneous panniculitic T-cell lymphomas with a γ/δ T-cell receptor phenotype are now distinguished from the less aggressive α/β panniculitic T-cell lymphoma. We describe a patient with deep ulcers initially diagnosed as pyoderma gangrenosum, which was reclassified as CGD-TCL. Local radiation followed by weekly infusions of denileukin diftitox put the patient into remission.

Denileukin diftitox

Denileukin diftitox

Cutaneous γ–δ T-cell lymphoma treated with radiation and denileukin diftitox

Cutaneous γ–δ T-cell lymphoma treated with radiation and denileukin diftitox

Durable complete remission of mycosis fungoides following erythroderma induced by denileukin diftitox

To the Editor: Carretero-Margolis and Fivenson 1 Carretero-Margolis C. Fivenson D. A complete and durable response to denileukin diftitox in a patient with mycosis fungoides. J Am Acad Dermatol. 2003; 48: 275-276 Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar described a patient with mycosis fungoides (MF) who achieved a durable complete response (CR) following diffuse erythroderma that developed during a second course of denileukin diftitox. We now report the case of a similar patient who experienced a CR that has lasted for more than 9 years.

Clinical Management of T-Cell Malignancies: Current Perspectives, Key Issues, and Emerging Therapies

Peripheral T-cell non-Hodgkin's lymphomas are a diverse group of disorders, most of which carry a poor prognosis. Relapse is common following the administration of most currently available agents, and there are few effective options for salvage therapy. This article discusses a number of novel emerging therapies for the treatment of patients with T-cell non-Hodgkin's lymphomas, including the antimetabolite nelarabine, the purine nucleoside phosphorylase inhibitor forodesine, the pyrimidine analogue gemcitabine, and the fusion protein denileukin diftitox. Other therapies discussed for the treatment of patients with T-cell non-Hodgkin's lymphomas include bendamustine, gallium nitrate, and bortezomib, as well as the mammalian target of rapamycin inhibitors, small molecules that target the apoptotic pathways, immunomodulatory agents, and monoclonal antibodies.

Denileukin Diftitox (ONTAK) Plus CHOP Chemotherapy in Patients with Peripheral T-Cell Lymphomas (PTCL), the CONCEPT Trial.

PTCL are an aggressive group of lymphomas comprising a number of histopathologic subtypes for which CHOP chemotherapy has been the standard first-line regimen at many centers. Denileukin diftitox (Dd) is a recombinant DNA-derived cytotoxic protein composed of diphtheria toxin fragments A and B and the full length sequence of human interleukin-2 (IL-2). Dd targets T-cells expressing the intermediate and high-affinity IL-2 receptor. Because the mechanism of action of Dd is distinct from traditional cytotoxic chemotherapy and Dd has exhibited minimal myelosuppression, we evaluated the safety, tolerability, and efficacy of combining Dd with CHOP as first-line therapy for patients with PTCL according to the REAL classification. (Pts with mycosis fungoides or Sezary syndrome were not included.) Dd was administered at 18 mcg/kg/day on Days 1 and 2 followed by CHOP on Day 3, and G-CSF support starting Day 4, every 3 weeks for up to 6 cycles. Evaluation of response is performed after every 2 cycles of treatment.Results: Forty-one pts, 18 male/23 female, have been enrolled to date, with a median age of 52. Ten pts are not evaluable for response: 5 discontinued due to an adverse event (AE) prior to assessment of response; 3 due to lack of measurable disease at baseline; and 2 are too early to evaluate. For the 31 response-evaluable patients, the overall response rate is 90%, with 71% (22/31) CR or CRu, 19% (6/31) PR, 6% (2/31) SD, and 3% (1/31) PD. Ten of 28 responders (36%) have progressed, with a median duration of response of 13 months.PTCL subtypeNo. of PatientsNo. evaluableResponsesORRPTCL-nos20153 CR, 5 CRu, 4 PR, 2 SD, 1 PD80%Angioimmunoblastic1093 CR, 5 CRu, 1 PR100%Anaplastic large cell642 CR, 2 CRu100%Enteric T-cell211 CRu100%Hepatosplenic10n/an/aNasal/nasal type T/NK cell111 CRu100%Subcutaneous panniculitic T-cell111 PR100%Toxicities have generally been grade 1–2, were transient, and caused few dose modifications. The most common have been fatigue (62%), nausea (44%), anemia (38%), sensory neuropathy (33%), hypoalbuminemia (33%), elevated ALT (30%), dyspnea (28%), thrombocytopenia (30%), leukopenia (28%), fever (25%), elevated AST (25%), lymphopenia (25%), and hyperglycemia (25%). Forty-three percent (17/40) of patients experienced one or more grade 3–4 hematological toxicities and 40% (16/40) of patients experienced one or more grade 3–4 non-hematological toxicities. Five patients discontinued the study due to AEs, all occurring prior to Cycle 2, for: infusion-related anaphylaxis; elevated LFTs; port-related staph sepsis; pneumonia; and a death possibly resulting from tumor lysis syndrome and rhabdomyolysis.Conclusion: The combination of Dd plus CHOP has a generally manageable safety profile and to date has exhibited promising clinical activity in PTCL.

Prognostic Factors in Primary Cutaneous Anaplastic Large Cell Lymphoma: Clinical and Molecular Characterization of a Subset with Worse Outcome.

Background and Objectives: Primary cutaneous anaplastic large cell lymphoma (pcALCL) has an overall favorable prognosis. However, we have previously suggested that patients with extensive limb involvement may have a worse outcome (J Am Acad Dermatol 49:1049, 2003). The primary objective was to assess the potential prognostic factors in pcALCL, in particular the role of extensive regional single-limb disease (ERSL-D), defined as presentation with or progression to T2b or T2c involvement of a single limb, or T3b involvement of > 3 contiguous body regions. Our secondary objectives were to study the gene expression profiles and treatment responses of our patients with pcALCL that may correlate with clinical outcome.Patients and Methods: This was a retrospective study involving 48 patients with pcALCL diagnosed and managed at Stanford from 1990–2005. The potential prognostic factors for overall and disease-specific survivals (OS and DSS) were analyzed using the KM method and univariate and multivariate Cox regression. Cox regression was also used to identify risk factors for progresson to extracutaneous disease. Gene expression profiles were studied using cDNA microarrays.Results: The OS and DSS rates of the entire cohort were 76% and 85% at 5 yrs and 70% and 85% at 10 yrs, respectively. Our univariate analysis demonstrated age, ERSL-D, and progression to extracutaneous disease (as a time-dependent variable) as significant prognostic factors for OS, while ERSL-D and progression to extracutaneous disease were significant for DSS. Sex, presence of spontaneous regression, and lesion site were not significantly assoicated with OS or DSS. Patients with T1 (solitary skin lesion) disease had an overall more favorable OS and DSS compared to those with T2 (regional skin involvement) and T3 (generalized skin involvement) disease, although the differences were not statisticlly significant. In our multivariate analysis, age (HR 1.83, 95% CI 1.02–3.26) and progression to extracutaneous disease (HR 6.42, 95% CI 1.39–29.68) remained significant for OS, while ERSL-D (HR 29.31, 95% CI 1.72–500.82) and progression to extracutaneous disease (HR 13.12, 95% CI 1.03–167.96) remained independent prognostic factors for DSS. Presentation with T3 disease was a significant risk factor for progression to extracutaneous disease (HR 10.20, 95% CI 1.84–56.72). Microarray studies of 14 samples from 3 ERSL-D and 7 classic pcALCL patients were performed. The patients with ERSL-D and classic pcALCL formed distinct, separate clusters. Classic pcALCL showed concurrent upregulation of epidermal genes analogous to normal skin, while ERSL-D lacked this signature. Genes upregulated in ERSL-D (after subtraction of epidermal genes) included STAT5A, IL2Rα, HIPK2, WDR10 and those down-regulated included RXRA. These gene profiling data suggest that targeting IL2R (denileukin diftitox) or STAT5 (HDAC inhibitors) may be appropriate in ERSL-D while therapeutic resistance to bexarotene may be linked to lack of RXRA gene expression.Conclusion: Our data suggest that patients with ERSL-D have a worse clinical outcome associated with a distinct gene expression profile. More aggressive and targeted treatments may be indicated in this subgroup.

Nasal NK/T Cell Lymphoma: Dramatic Response to Pegaspargase in Two Patients.

Nasal NK/T cell lymphoma is a rare type of non-Hodgkin lymphoma (NHL) in the United States for which treatment has been unsatisfactory. NK/T cell lymphoma is common in Asia and is highly associated with EBV. Recognized as a distinct clinicopathological entity of NHL expressing NK-cell or cytotoxic T cell markers, it usually presents in the mid facial region, but may also rarely present in other extranodal sites such as the skin or gastrointestinal tract. Being so infrequent in the USA, prospective clinical trials are not feasible for NK/T cell lymphoma. Traditionally, it has been treated with irradiation with or without CHOP-like chemotherapy. Prognosis is poor with 5 year overall survival of 30–44%. About 60% of patients have clinically aggressive disease and are frequently refractory to conventional chemotherapy. We report 2 patients diagnosed with nasal NK/T cell lymphoma refractory to CHOP treatment, treated at Fox Chase Cancer Center with single agent pegaspargase (Oncaspar), a pegylated form of L-asparaginase. We selected this based on reports from Japan and China of activity of L-asparaginase in this disease. Yong et al (Hematol Oncol 2006) treated 33 NK/T lymphoma patients whose disease had failed to respond to, or progressed on, CHOP with an L-asparaginase based regimen plus involved field irradiation and reported a 52% CR rate. Patient 1 is a 64-year-old Caucasian woman who presented with a lesion on her left buttocks, biopsy of which revealed NK/T lymphoma. She was treated with loco-regional irradiation and CHOP. Soon after, she developed new lesions on her lower extremities as well as a nasal mass, and biopsy again confirmed nasal NK/ T cell lymphoma. Flow cytometry showed cytoplasmic CD3+, CD56+, and CD25+. Of note, tumor cells were negative for EBV (LMP1) by immunohistochemistry but in situ hybridization was not performed. TIA-1 was diffusely positive. She received radiation for the nasal mass and was initially started on denileukin diftitox, but developed a capillary leak syndrome with pulmonary edema, and after treatment was stopped, she developed progressive disease with extensive and ulcerated lower extremity lesions. With pegaspargase treatment, she had a dramatic improvement of her skin lesions. She completed 4 cycles, the last of which was complicated by an anaphylactic reaction and further treatment was held. Patient 2 is a 48 year old Asian man who presented with a left nasal cavity mass. Biopsy was consistent with nasal NK/T cell lymphoma, expressing CD 3, CD 2, CD8, CD 56, TIA-1 and EBV early RNA. The mass was partially resected and then treated with radiation therapy with complete resolution. He then received CHOP, but CT scan following his fourth cycle showed multiple liver lesions, the largest measuring 2.5 cm. A core biopsy again was consistent with nasal NK/T cell lymphoma. The patient was initiated on pegaspargase with nearly complete resolution of the hepatic lesions following 3 infusions and continues on treatment. L- asparaginaase has activity in this rare disease and further exploration alone or in combination is warranted.

A Multicenter Clinicopathologic Experience of HTLV-1 ATLL: A Retrospective 15 Year Review Reveals Little Progress.

Adult T cell Leukemia/Lymphoma (ATLL) is a rare manifestation of Human T-Lymphotropic Virus type 1 (HTLV-1) which is endemic in Japan, the Caribbean, and regions of Africa and Latin America. Endemic regions have also been identified in the US, primarily where immigrants of endemic countries reside. The NYC metropolitan area has the greatest number of Caribbean-born immigrants to the US which has formed the basis for this retrospective review. A diagnosis of ATLL was made according to the following criteria: a clinical history consistent with ATLL; a positive HTLV-1 antibody by ELISA and Western Blot, or evidence of HTLV-1 proviral integration by PCR; and histological findings compatible with ATLL. A total of 89 patients were identified at 3 institutions in NYC from 8/92 to 5/07. There were 37 men and 52 women with a median age of 50y (range 22 to 82y). All but 6 patients had immigrated to the US from the Caribbean, Latin America or Africa, and the majority were from Jamaica (25.8%) and the Dominican Republic (19.1%). The acute subtype predominated (68.5%), followed by the lymphomatous (20.2%), chronic (6.8%) and smoldering (4.5%) subtypes. The most common presenting symptoms were lymphadenopathy (80.9%) and skin rash (39.3%) and the median ECOG performance status was 3. WBC counts ranged from 3.0 to 334.0 x 109/l (median of 12.5 X 109/l). Hypercalcemia was seen in 71.9% of patients (median calcium level of 13.5 mg/dl, range 9.8 to 27.0 mg/dl). Twenty-eight patients (31.5%) had CNS involvement during their course. The median International Prognostic Index (IPI) was 4. Most patients received a combination-alkylator based chemotherapy regimen in the frontline setting (ex: CHOP) (61.3%), with an overall response rate (ORR) to the frontline treatment of 58.2%. Twenty patients (20.2%) received AZT and IFN at sometime during their course with an ORR of 25%. Twelve patients (13.5%) received a biologically based therapy at sometime during their course, with only two patients achieving a partial response (to alemtuzamab and denileukin diftitox). Despite initial responses to therapy, the median overall survival for all subtypes was 6 mos (range 0.5 to 78.5 mos). Median survival for specific subtypes was noted to be: 4 mos for the acute subtype (range 0.5 to 78.5 mos); 9 mos for the lymphomatous subtype (range 1 to 63 mos), 17 months for the chronic subtype (range 5 to 22 mos) and 34 mos for the smoldering subtype (range 16 to 48 mos).Conclusion: This retrospective series represents one of the largest North American experiences to date among primarily Caribbean descendants. Interestingly, when placed into the context of other experiences published over the past 30 years, it is clear there has been little to no change in the outcome of patients diagnosed with this disease. In fact, this population, with a median overall survival of only 6 mos, represents one of the poorest outcomes reported for any sub-type of lymphoma. These data suggest that radically new ATLL directed therapies are needed. The recent development of several new T-cell active agents, in addition to other strategies (ex: transplantation) need to be specifically studied in this population.

IL-2 immunotoxin denileukin diftitox reduces regulatory T cells and enhances vaccine-mediated T-cell immunity

AbstractCD4+CD25+Foxp3+ regulatory T (Treg) cells have been implicated in the lack of effective antitumor immunity. Denileukin diftitox (DAB389IL-2), a fusion protein of interleukin 2 (IL-2) and diphtheria toxin, provides a means of targeting Treg cells. In this study, we examined (1) the effect of denileukin diftitox on the deletion of Treg cells in various lymphoid compartments and (2) the dose scheduling of denileukin diftitox in combination with a recombinant poxviral vaccine to enhance antigen-specific immune responses. Treg cells in spleen, peripheral blood, and bone marrow of normal C57BL/6 mice were variously reduced after a single intraperitoneal injection of denileukin diftitox; the reduction was evident within 24 hours and lasted approximately 10 days. Injection of denileukin diftitox 1 day before vaccination enhanced antigen-specific T-cell responses above levels induced by vaccination alone. These studies show for the first time in a murine model (1) the differential effects of denileukin diftitox on Treg cells in different cellular compartments, (2) the advantage of combining denileukin diftitox with a vaccine to enhance antigen-specific T-cell immune responses, (3) the lack of inhibition by denileukin diftitox of host immune responses directed against a live viral vector, and (4) the importance of dose scheduling of denileukin diftitox when used in combination with a vaccine.

Treatment of systemic mastocytosis with denileukin diftitox

American Journal of HematologyVolume 82, Issue 12 p. 1124-1124 Letter to the American Journal of HematologyFree Access Treatment of systemic mastocytosis with denileukin diftitox Alfonso Quintás-Cardama, Alfonso Quintás-Cardama Department of Leukemia, The University of Texas M. D. Anderson Cancer Center, Houston, TexasSearch for more papers by this authorHagop Kantarjian, Hagop Kantarjian Department of Leukemia, The University of Texas M. D. Anderson Cancer Center, Houston, TexasSearch for more papers by this authorSrdan Verstovsek, Srdan Verstovsek Department of Leukemia, The University of Texas M. D. Anderson Cancer Center, Houston, TexasSearch for more papers by this author Alfonso Quintás-Cardama, Alfonso Quintás-Cardama Department of Leukemia, The University of Texas M. D. Anderson Cancer Center, Houston, TexasSearch for more papers by this authorHagop Kantarjian, Hagop Kantarjian Department of Leukemia, The University of Texas M. D. Anderson Cancer Center, Houston, TexasSearch for more papers by this authorSrdan Verstovsek, Srdan Verstovsek Department of Leukemia, The University of Texas M. D. Anderson Cancer Center, Houston, TexasSearch for more papers by this author First published: 01 November 2007 https://doi.org/10.1002/ajh.21013Citations: 8AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Citing Literature Volume82, Issue12December 2007Pages 1124-1124 ReferencesRelatedInformation

Management of advanced-stage peripheral T-cell lymphomas

Peripheral T-cell lymphomas (PTCLs), several entities with great clinical, histologic, and biologic heterogeneity, represent 8% to 15% of all malignant lymphomas. With current treatment regimens, 5-year survival is only about 30% to 35%. Outcome is poorer with PTCL than with aggressive B-cell lymphoma because of more frequent adverse clinical features at diagnosis, a lower response rate to chemotherapy, and a higher incidence of relapses, but it is also known that the T-cell phenotype itself is associated with a poor prognosis independent of other prognostic factors. Initial treatment of patients with advanced-stage PTCL mostly consists of six to eight courses of anthracycline-based chemotherapy such as CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone). In fit elderly patients, standard therapy is still six cycles of CHOP-14, but up-front consolidation with intensive chemotherapy and autologous stem cell transplantation are often used in younger patients. The humanized CD52 monoclonal antibody alemtuzumab has shown activity in some T-cell malignancies; with appropriate antibiotic and virostatic prophylaxis, its use seems feasible for PTCL, both as a single agent and in conjunction with chemotherapy. New drugs such as denileukin diftitox, histone deacetylase inhibitors, and pralatrexate have shown promising activity in PTCL.

Efficacy of Denileukin Diftitox in Subcutaneous Panniculitis-Like T-Cell Lymphoma

Subcutaneous panniculitis-like lymphomas (SPTCLs) are a heterogeneous group of diseases characterized by pleomorphic lymphocytes infiltrating the subcutis in a lobular panniculitis-like pattern. Characterization of SPTCL based on T-cell phenotype has prognostic significance in that most patients with the α/β T-cell phenotype of SPTCL demonstrate clinically indolent behavior, whereas those with γ/δ variant typically manifest more aggressive disease. In the past, traditional therapies have included single-agent or systemic multi-agent chemotherapy with or without radiation therapy, immunosuppressive therapies, or, in refractory patients, bone marrow transplantation. We describe complete clinical regression of disease and a median response duration of > 6 months in 2 patients with SPTCL treated with corticosteroids and denileukin diftitox. Furthermore, the addition of bexarotene to denileukin diftitox restored a clinical response in 1 of the patients after disease progression, suggesting the activity of this combination in patients with SPTCL.

Forkhead box P3-positive regulatory T cells in immune surveillance and cancer

Sir, According to Betts et al (2007), immune surveillance would be limited by the inhibitory effect of naturally occurring forkhead box P3 (FOXP3)-positive (+) regulatory T cells. In mice, methylcholanthrene-induced fibrosarcomas were strikingly infiltrated with FOXP3+ regulatory T cells. The partial ablation of FOXP3+ regulatory T-cell activity resulted in a marked reduction in tumour incidence. Increased frequencies of CD4+CD25high T regulatory (Treg) cells have been registered in the peripheral blood of patients with several types of cancer, suggesting a putative role exerted by these cells in tumour escape from immunological control. There is a significant increased frequency of CD4+CD25high T cells in patients with renal cell carcinoma compared with normal donors (Griffiths et al, 2007). These data were confirmed using the FOXP3 marker of Treg cells in a subset of these patients and normal donors. The early follow-up data showed an association between higher peripheral blood Treg cells count and adverse overall survival (Griffiths et al, 2007). Similarly, an expansion of increase of FOXP3+CD4+CD25high Treg cells in peripheral blood and tumour microenvironment has been demonstrated in nasopharyngeal carcinoma (NPC) patients (Lau et al, 2007). The expanded Treg in the circulation also showed enhanced suppressive activity on CD4+CD25− T-cell proliferations. The increase of this functional Treg population would be able to reduce T-cell-mediated antitumour immunity, since a significant decrease in CD4+ T-cell populations in NPC patients was observed (Lau et al, 2007). Ipilimumab, a fully human anticytotoxic T lymphocyte-associated antigen-4 (CTLA-4) monoclonal antibody, depresses T regulatory (Treg) cell numbers without increasing vaccine-specific CD8+ T-cell responses in patients previously treated with investigational anticancer vaccines (O'Mahony et al, 2007). Treg cells, detected by expression of CD4+CD25+CD62L+, decreased at early time points after ipilimumab administration, with a rebound increase by the time of the next treatment. Tumour responses were limited to two patients with non-Hodgkin's lymphoma who experienced limited tumour regression at selected metastatic sites. In one of these patient responders, reverse transcription–polymerase chain reaction for FOXP3 mRNA expression among peripheral blood mononuclear cells showed that FOXP3 expression declined at early time points after ipilimumab administration and rebounded to baseline values by the time of the next infusion (O'Mahony et al, 2007). CD4+CD25+FOXP3+ Treg cells are involved in the maintenance of suppressive control of aberrant immune responses. Mutations in FOXP3 cause multi-organ autoimmunity in both human and mouse (Marson et al, 2007). CD4+CD25+FOXP3+ Tregs may impede the development of effective immunity to autologous tumour cells (Yamaguchi and Sakaguchi, 2006), since self-reactive T cells are continuously suppressed by Treg cells. When suppression is relieved, self-reactive T cells become activated and facilitate accelerated maturation of dendritic cells (Kim et al, 2007). In fact, the immunisation of mice against FOXP3 elicits a robust FOXP3-specific CTL response, enhancing vaccine-induced antitumour immunity (Nair et al, 2007). The combined CD4+CD25+ regulatory T-cell inactivation and genetic vaccination resulted in significant tumour protection in a metastatic tumour model (Elia et al, 2007). In another murine model, it has been demonstrated that combining denileukin diftitox, a fusion protein of interleukin-2 and diphtheria toxin, with a vaccine enhances antigen-specific T-cell immune responses (Litzinger et al, 2007). Molecules upregulated on the surface of Treg cells, such as CTLA-4 and CD25, are not expressed exclusively on Tregs (Fontenot and Rudensky, 2004, 2005; Sakaguchi, 2004). The effectiveness of targeting CD25 to eliminate Treg is limited by the fact that CD25, the low-affinity interleukin-2 receptor, is upregulated on conventional antigen-activated T cells (Fontenot and Rudensky, 2004). The only gene product known to be exclusively expressed in Tregs of mice is FOXP3 (Fontenot and Rudensky, 2004). On the other hand, even though FOXP3 expression was initially thought to be restricted to the CD4+CD25+ regulatory T-cell population, recent studies in B-cell non-Hodgkin's lymphoma showed that a subset of intratumoural but not peripheral CD4+CD25− T cells express FOXP3 and are capable of suppressing the proliferation of autologous infiltrating CD8+ T cells (Yang et al, 2007). Nevertheless, based on the findings reported by Betts et al (2007), FOXP3-positive Treg cells could represent an important therapeutic target for cancer. The results of this study suggest a role for Tregs in suppressing effective immune surveillance of carcinogen-induced tumours in intact animals. Moreover, besides the enhanced antitumour immunity, the FOXP3 vaccination could lead to the preferential depletion of intratumoural but not peripheral Treg, eventually reducing the risk of autoimmunity (Nair et al, 2007). However, further studies are needed to better clarify the weight of Treg depletion within the global immune response to the tumour.

Sustained Hematologic and Central Nervous System Remission with Single-Agent Denileukin Diftitox in Refractory Adult T-Cell Leukemia/Lymphoma

Human T-lymphotrophic virus–1–associated adult T-cell leukemia/lymphoma (ATLL) is a rare and often fatal disease. Initials treatment often includes zidovudine/interferon (IFN)–based therapy, although disease remission is typically not complete or durable. This study reports on a 55-year-old man with relapsed/refractory leukemic-phase ATLL including significant central nervous system (CNS) disease with resistance to previous zidovudine/IFN and arsenic trioxide/IFN treatment. The patient experienced a rapid hematologic and CNS clinical response with single-agent denileukin diftitox therapy (18 μg/kg per day for 5 days). He tolerated 8 cycles of denileukin diftitox therapy well and experienced a sustained complete hematologic and CNS remission. The patient subsequently underwent matched sibling reduced-intensity allogeneic transplantation and remains disease free. Further study examining denileukin diftitox in patients with relapsed/refractory ATLL is warranted.

Phase II trial of the combination of denileukin diftitox and rituximab for relapsed/refractory B‐cell non‐Hodgkin lymphoma

Denileukin diftitox plus rituximab was evaluated in relapsed/refractory B-cell non-Hodgkin lymphoma patients. Of the 38 evaluable patients, 30 (80%) were rituximab-refractory. The overall response rate (ORR) was 32%, with six complete responses (CR) and six partial responses (PR). The median time to progression for responders was 8 months (range: 2-36+); two patients with rituximab-refractory follicular lymphoma were in CR at 25 and 36+ months. The ORR was 55% (4 CRs, 2 PRs) in 11/14 patients with rituximab-refractory follicular lymphoma, and 100% in the three patients with rituximab-sensitive tumour. Most toxicities were low grade and transient, and myelotoxicity was uncommon.

Efficacy and safety of denileukin diftitox (Dd) in a phase III, double-blind, placebo-controlled study of CD25+ patients with cutaneous T-cell lymphoma (CTCL)

8026 Background: ONTAK®(Dd), a genetically engineered fusion protein combines the enzymatically active domain of diphtheria toxin with the sequence of interleukin-2 (IL-2), designed to target IL-2 receptor expressing malignancies. Dd received FDA accelerated approval for the treatment of CTCL in patients with the CD25 component of the IL-2 receptor. Methods: The confirmatory placebo- controlled L4389–11 phase III trial evaluated 9 and 18μg/kg/d Dd in 144 patients with CD25(+) CTCL. Patients (=3 prior treatments, stages Ia - III) received Dd or placebo IV for up to 8 cycles, consisting of Dd once daily for 5 days every 3 weeks. Tumor burden in skin, blood and lymph nodes and a physician's global (PGA) were assessed relative to baseline and before every treatment cycle beginning with cycle 2. Confirmation of tumor response required two more consecutive cycles (3 observations). Investigator assessments were ratified by an independent Drug Evaluation Review Committee. Results: Initial analysis of activity and benefit shown below. Both Dd treatment arms were greatly superior to placebo in a dose dependent fashion. Population demographics were the same across treatment arms (median age 59 years, 55% male). Randomization was stratified by disease status at baseline, 67% were = stage IIa, 33% were =stage IIb. Response between stage groups within each arm did not differ significantly. Many responses were confirmed after 5 or more cycles. AEs were similar to those in previous Dd studies. The only significantly different Grade 3/4 adverse event was nausea (2% in Placebo and 15% in 18μg/kg/d). No differences in serious adverse events among treatment arms were observed. The frequency of AEs and SAEs markedly decrease after the first two cycles of treatment. Conclusions: This is the largest randomized, placebo controlled trial conducted in CTCL, providing clear evidence for efficacy and clinical benefit for Dd. No significant financial relationships to disclose. [Table: see text]

Receptor expression in orbital inflammatory syndromes and implications for targeted therapy

To investigate the expression of multiple therapeutic targets in tissue specimens from patients with orbital inflammatory syndromes, the clinical records of 16 patients treated for orbital inflammation between January 2003 and November 2005 for whom tissue blocks were available were reviewed retrospectively. Immunohistochemical staining was performed on archived specimens using commercially available monoclonal antibodies against CD3, CD20, CD22, CD23, CD25, and CD52 antigens. The histologic diagnoses were confirmed, and the immunohistochemical staining patterns were agreed upon by both collaborating pathologists (JLJ and PC-B). The study included 13 women and 3 men who ranged in age from 4 to 79 years (mean, 46 years). The histologic diagnoses were as follows: orbital pseudotumor in six patients; sarcoidosis, three; eosinophilic granuloma, one; necrobiotic xanthogranuloma, one; nonspecified granulomatous inflammation, one; Graves' ophthalmopathy, one; Wegener's granulomatosis, one; and reactive lymphoid hyperplasia, two. One orbital lymphoma specimen and one foreign body reaction specimen were used as controls. CD20 was strongly expressed in all specimens except three (Wegener's granulomatosis, eosinophilic granuloma, and nonspecified granulomatous inflammation specimens), and CD25 was strongly expressed in all specimens except the Wegener's granulomatosis specimen, in which this antigen was only moderately expressed. CD20 and CD25 were strongly or moderately expressed in most of the tested specimens of orbital inflammation. If our findings are confirmed in a larger study, rituximab, which targets CD20, and denileukin diftitox (ONTAK), which targets CD25, should be considered for future clinical trials for orbital inflammatory syndromes.